The objectives of this proposal are to determine the role of the bronchial circulation in modulating airway smooth muscle tone and the role of ventilation in controlling bronchial blood flow. Whether the bronchial circulation can modulate airway resistance changes due to cold air challenge and bronchoconstrictor agents will be determied. Cold air induced bronchospasm in susceptible individuals is hypothesized to reflect a failure of the bronchial circulation to provide warming and humidification of inspired air. To study this hypothesis we have developed an animal model which responds to cold air and in which the bronchial circulation can be precisely controlled. Because the control of the bronchial circulation is poorly understood, we also propose to use this model to determine the influence of airway pressure and respiratory gases on regulating bronchial blood flow. All experiments will be performed on anesthesized sheep, mechanically ventilated and instrumented to monitor total pulmonary and small airways resistance. Because of the unique anatomy of the sheep bronchical vasculature, we have developed a new approach to control and study bronchial blood flow. The procedures involve cannulation and perfusion of the main bronchial artery. Measurement of bronchial artery pressure at known flow rates thereby provides a continuous measure of bronchial vascular tone. Experimental protocols are designed to test several specific aims. We shall investigate the direct effects of bronchial blood flow on the airway response to cold air hyperventilation. We will also study one purported mechanism by which cold air bronchoconstriction can occur. This mechanism involves thermal stimulation of mast cells resulting in mediator release. We have also demonstrated that recovery of airway tone following a histamine challenge is affected by the magnitude of the bronchial circulation. Experiments are designed to assess the relative importance of the bronchial circulator in clearance of bronchoactive agents. Preliminary results have also shown that the bronchial circulation is unusually sensitive to changes in airway pressure. We intend to further investigate the role of this response in regulating bronchial blood flow and to determine its mechanism. Because the bronchial circulation has been difficult to study, its role in airway function is not well defined. The results of the proposed experiments are designed to clarify this role and aid in our understanding of the underlying pathophysiology of diseases of airways reactivity.